Pharmaceutical Companiesand Research Publications

Daniel Kracov

October 28, 2008Pharmaceutical Regulatory and Compliance Congress and Best Practices ForumMorning Track V: Emerging Compliance Challenges

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Challenges and Tensions in Framing Good Publication Practices (GPPs)

Volume of studies for publication

Time commitments of leading researchers

Pressure to get data into publications

Production of high-quality manuscripts

Relative interest in negative studies

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Challenges and Tensions in Framing Good Publication Practices (GPPs)

Invalid or “failed” studies

Proprietary concerns

Timing of publication

Role of medical writing companies

Investigator-sponsored studies

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Focus on Pharmaceutical Company Publication Practices

Expansion of ClinicalTrials.gov post-FDA Amendments Act

Scrutiny of Responses to Unsolicited Requests From Physicians

Growing Importance of Compendia for Product Coverage (e.g., Oncology)

Industry Payments to Physicians and Potential Conflicts of Interest

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FDA and “Good Reprint Practices”

Food and Drug Administration (FDA) Draft Guidance on Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices (GRR Draft Guidance)

– Published in peer-reviewed journals, and not including supplements or other publications paid for by the manufacturer

– Not false or misleading

– Not abridged or summarized by manufacturer

– Accompanied by approved labeling, bibliography, and (if called into question by another study) a representative contrary article

– Distributed separately from promotional materials

– Accompanied by disclaimers and disclosures

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Congressional Scrutiny

Letter from Chairman Henry Waxman (D-CA), House Committee on Oversight and Government Reform (November 30, 2007) to FDA Objecting to GRR Draft Guidance

– Companies “can manipulate and selectively distribute studies in order to make their products appear safer and more effective than they truly are.”• “Systematically suppressed studies”

• Studies…were distorted…”

• “Omitted important …data”

• Study “reported only six months of data despite having collected 12 months of data”

• “Distribution of the early peer-reviewed journal articles could have led to many unnecessary deaths”

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Congressional Scrutiny

Letter from Chairman Henry Waxman (D-CA), House Committee on Oversight and Government Reform (November 30, 2007) to FDA Objecting to GRR Draft Guidance (cont’d)

– False Claims Act settlements “reveal that use of publications to promote off-label uses is a concerted strategy”

– “There is abundant evidence that industry-funded published studies are overwhelmingly more likely to show favorable results than independently-funded studies.”

– “There are severe limitations inherent in the peer review process”• Lack of access to the study protocol or underlying data

• Peer reviewers do not necessarily have the time or expertise in all aspects of the subject matter

• Journals cannot guarantee the correctness or authenticity of the article, or detect fraudulent or flawed research

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Industry Principles

PhRMA Principles on the Conduct of Clinical Trials and Communication of Clinical Trial Results – Publications Provisions– Ensure the accuracy and integrity of the entire study database

– Exploratory Studies• “Sponsors do not commit to publish the results of every exploratory study

performed, or to make the designs of clinical trial protocols available publicly at inception.”

• “If information from an exploratory study is felt to be of significant medical importance, sponsors should work with the investigators to submit the data for publication”

– “In all cases, the study results should be reported in an objective, accurate, balanced and complete manner, with a discussion of the strengths and limitations of the study.”

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Industry Principles

PhRMA Principles on the Conduct of Clinical Trials and Communication of Clinical Trial Results – Publications Provisions (cont’d.)

– Authorship -- Consistent with International Committee of Medical Journal Editors and major journal guidelines

• “Anyone who provides substantial contributions to the conception or design of a study, or data acquisition, or data analysis and interpretation; and writing or revising of the manuscript; and has final approval of the version to be published should receive appropriate recognition as an author or contributor when the manuscript is published.”

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Industry Principles

PhRMA Principles on the Conduct of Clinical Trials and Communication of Clinical Trial Results – Publications Provisions (cont’d.)

– Authorship• “Companies sometimes employs staff to help analyze and interpret

data, and to produce manuscripts and presentations. Such personnel must act in conjunction with the investigator-author.”

– Contributions should be recognized in publications – as named author, contributor, or acknowledgements depending upon level of contribution

• “All authors, whether from within a sponsoring company or external, will be given the relevant statistical tables, figures, and reports needed to support the planned publication.”

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Industry Principles

PhRMA Principles on the Conduct of Clinical Trials and Communication of Clinical Trial Results – Publications Provisions (cont’d.)

– Related Publications• For a multi-site trials, analyses based on single-site data have

significant statistical limitations, and frequently do not provide meaningful information

– Such reports should not precede and should always reference the primary presentation of paper of the entire study

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Industry Principles

PhRMA Principles on the Conduct of Clinical Trials and Communication of Clinical Trial Results – Publications Provisions (cont’d.)

– Investigator Access to Data and Review of Results• As owners of the study database, sponsors have discretion to

determine who will have access to the database

• Generally, study databases are only made available to regulatory authorities – but subject to exceptions --

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Industry Principles

PhRMA Principles on the Conduct of Clinical Trials and Communication of Clinical Trial Results – Publications Provisions (cont’d.)

– Investigator Access to Data and Review of Results• Exceptions:

– Individual investigators will have their own participants’ data, and will be provided the randomization code after trial conclusion

– Sponsors will make a summary of the study results available to investigators

– Any investigator who participated in the conduct of a multi-site trial will be able to review relevant statistical tables, figures, and reports for the entire study at the sponsor’s facilities, or other mutually agreeable location

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Industry Principles

PhRMA Principles on the Conduct of Clinical Trials and Communication of Clinical Trial Results – Publications Provisions (cont’d.)

– Sponsor Review• “Sponsors have a right to review any manuscripts, presentations, or

abstracts that originate from [their] studies or that utilize [their] data before they are submitted for publication or other means of communication”

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Industry Principles

PhRMA Principles on the Conduct of Clinical Trials and Communication of Clinical Trial Results – Publications Provisions (cont’d.)

– Sponsor Review• “Sponsors commit to respond in a timely manner, and not to

suppress or veto publications or other appropriate means of communication (in rare cases it may be necessary to delay publication and/or communication for a short time to protect intellectual property).”

• “Where differences of opinion or interpretation of data exist, the parties should try to resolve them through appropriate scientific debate”

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Industry Principles

PhRMA Principles on the Conduct of Clinical Trials and Communication of Clinical Trial Results – Publications Provisions (cont’d.)

– Journal Review• “If requested by a medical journal when reviewing a submitted

manuscript for publication, the clinical trial sponsor will provide a synopsis of the clinical trial protocol and/or pre-specified plan for data analysis with the understanding that such documents are confidential and should be returned to the sponsor.”

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Other Sources of GPP Guidance

International Committee of Medical Journal Editors (ICMJE)– Uniform Requirements for Manuscripts Submitted to Biomedical

Journals: Writing and Editing for Biomedical Publication; Publication Ethics: Sponsorship, Authorship, and Accountability (updated October 2008) at http://www.icmje.org/

World Association of Medical Editors (WAME)– Policy statements at http://www.wame.org/resources/policies

Committee on Publication Ethics (COPE)– Guidelines on Good Publication Practice at

http://www.publicationethics.org.uk/guidelines

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Other Sources of GPP Guidance

American Medical Writers Association Code of Ethics and Position Statement on the Contributions of Medical Writers to Scientific Publications (www.amwa.org)

Wager, Field & Grossman, “Good Publication Practice for Pharmaceutical Companies” Current Medical Research and Opinions (19:149-154 (2003)

CONSORT (Consolidated Standards for Reporting Trials) Statement– http://www.consort-statement.org/

CSE's White Paper on Promoting Integrity in Scientific Journal Publications (2006)– http://www.councilscienceeditors.org/editorial_policies/white_paper.cfm

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Guidance From Settlement Provisions

Recent Settlements Increasingly Focused on Ghostwriting, Dissemination of Reprints, and Unsolicited Request Processes – e.g., State settlements with:

• Pfizer on Celebrex®/Bextra® (October 23, 2008)

• Eli Lilly on Zyprexa® (October 6, 2008)

• Merck on Vioxx® (May 20, 2008)

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Points to Consider in Developing and Refining Publication Policies

Publication Plans

Roles of Marketing, Medical Affairs, Product Team, Compliance, Legal, etc.

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Points to Consider in Developing and Refining Publication Policies

Role of Medical Writers

Agreements and Communications with Medical Writing Companies

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Points to Consider in Developing and Refining Publication Policies

Authorship and “Ghostwriting”

Investigator Agreements

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Points to Consider in Developing and Refining Publication Policies

Disclosures

Documenting Reasons for Delayed Publication

Duplicate or Redundant Publications

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Points to Consider in Developing and Refining Publication Policies

Risk Tolerance in Use of Reprints

Unsolicited Request Controls

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Points to Consider in Developing and Refining Publication Policies

Consistency of Application of Policies – SOPs

Tracking, Monitoring and Auditing

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Daniel A. KracovArnold & Porter LLP555 12th Street, N.W.

Washington, D.C. 20004

daniel.kracov@aporter.com(202) 942-5120